SEARCH

SEARCH BY CITATION

Abbreviations
E. coli

Escherichia coli

R. equi

Rhodococcus equi

A 4-day-old Thoroughbred filly was presented to Hagyard Equine Medical Institute for acute onset of diarrhea. Immunoglobulin concentrations at 24 hours of age had indicated adequate passive transfer. The filly had been apparently healthy until developing diarrhea at 4 days of age.

On presentation, the foal was lethargic and moderately dehydrated. Hematologic and biochemical analysis was unremarkable with the exception of mild hyponatremia (126 mEq/L; normal, 133–140 mEq/L), attributed to intestinal secretion, loss, or both. Abdominal ultrasound examination identified fluid intestinal contents. Fecal diagnostic tests including rotavirus PCR, Clostridium difficile toxins A and B ELISA, Clostridium perfringens enterotoxin ELISA, and Salmonella culture were negative. Aerobic and anaerobic blood cultures yielded no growth. The foal responded favorably to 7 days of supportive treatment with IV fluids, penicillin1 (22,000 IU/kg IV q6h), amikacin2 (25 mg/kg IV q24h), and metronidazole3 (15 mg/kg PO q8h). At discharge, the foal was clinically improved with normal manure. No recurrences of diarrhea were reported in the weeks after discharge.

The foal was presented again to the hospital at 73 days of age for acute onset of fever (102.9°F), blindness, and staggering. Flunixin meglumine4 (1.1 mg/kg IV) and dexamethasone5 (0.1 mg/kg IV) were administered on the farm. On presentation, the foal was febrile (101.6°F) and tachycardic (76 beats per minute) with hyperemic mucous membranes and prolonged capillary refill time. The foal was obtunded and circled the stall continuously, occasionally walking into objects and falling. Menace responses were absent with intact pupillary light reflexes bilaterally, indicating cortical blindness. The remainder of the cranial nerve examination was unremarkable. Neither head tremor nor obvious dysmetria was observed. General proprioceptive tests and postural reactions were difficult to assess because of the foal's altered mentation and resistance to restraint. No obvious signs of spinal ataxia were noted. The foal displayed no affinity for the mare and had no interest in nursing. No evidence of trauma was noted. Based on the neurologic examination, the foal's clinical signs were neuroanatomically localized to the prosencephalon.

Hematologic and biochemical analysis identified leukocytosis (28,000/μL; normal, 5000–12,600/μL) characterized by mature neutrophilia (20,100/μL; normal, 2800–8200/μL), hyperfibrinogenemia (800 mg/dL; normal, 200–500 mg/dL), and thrombocytosis (1,579,000/μL; normal, 115,000–450,000/μL), all suggestive of systemic infection, inflammation, or both. Blood ammonia concentration (203 μmol/L; normal, 0–63 μmol/L) and bile acid concentration (65 μmol/L; normal, 7.4–19.4 μmol/L) both were abnormally high. Aspartate aminotransferase, sorbitol dehydrogenase, γ- glutamyltransferase activity, and bilirubin concentration were within the reference range. Abdominal ultrasound examination identified increased echogenicity of the liver. The portal vein was not visualized and no other abdominal abnormalities were noted, although the foal's altered mentation and resistance to restraint prevented thorough sonographic evaluation. Hyperammonemic encephalopathy was diagnosed based on clinical and laboratory findings. Congenital portosystemic shunt, liver disease (eg, Tyzzer's disease, cholangiohepatitis), toxic hepatopathy (eg, iron intoxication, ingestion of toxic plants), intestinal hyperammonemia, and homocitrullinuria syndrome were considered as possible causes.

Homocitrullenuria syndrome has not been reported in Thoroughbred foals and there were no signs of gastrointestinal disease to support a diagnosis of intestinal hyperammonemia. Normal hepatic enzyme activities made primary hepatocellular or biliary disease unlikely. Portosystemic shunt was suspected based on age, hyperammonemia, and increased bile acid concentration, but the fever, leukocytosis, and hyperfibrinogenemia were not characteristic of a congenital anomaly.

Medical treatment was initiated with IV fluids (Plasma-Lyte6 with 5% dextrose), penicillin1 (22,000 IU/kg IV q6h), gentamicin7 (6.6 mg/kg IV q24h), ascorbic acid (25 g IV q24h), thiamine (10 mg/kg IV q12h), metronidazole3 (15 mg/kg PO q8h), lactulose (0.2 ml/kg PO q6h), pentoxifylline (7.5 mg/kg PO q8h), and vitamin E8 (20 U/kg PO q24h). On day 2 of hospitalization, the foal was brighter with intact menace responses bilaterally, suggesting resolution of cortical blindness, but continued to show signs of encephalopathy including head pressing, star gazing, and wandering. Rectal temperature remained increased at 102.6°F. Blood ammonia concentrations had decreased to 140 μmol/L. On day 3, the foal remained febrile (102.9°F) and was more stuporous than the previous day. A CBC indicated improving leukocytosis (18,500/μL), characterized by a mature neutrophilia (13,300/μL). Fibrinogen concentration remained increased at 600 mg/dL. Blood ammonia concentration had increased to 183 μmol/L. The dosing interval of lactulose was increased to every 4 hours in an attempt to resolve the persistent hyperammonemia.

Cerebrospinal fluid collected from the atlantooccipital space was cytologically normal with normal cell count and protein concentrations, and yielded no growth on culture. Histopathologic examination of a transcutaneous needle liver biopsy disclosed mild nonsuppurative portal hepatitis with portal tract atrophy. Portal infiltrates of mononuclear cells were present in low to moderate numbers. Portal areas were undersized with small or absent portal veins and contracted bile ducts. Hepatocytes essentially were normal with no evidence of fibrosis or hepatocellular necrosis. These findings were suggestive of mild portal inflammation and portosystemic shunting. Culture of a biopsy specimen of liver yielded Escherichia coli. Based on sensitivity profile, aminoglycoside treatment was switched to amikacin2 (25 mg/kg IV 24h).

On days 4–6 of hospitalization, the foal was increasingly somnolent without appreciable clinical improvement. Blood ammonia concentrations decreased to 65 μmol/L on day 5, but increased to 105 μmol/L on day 6. Bile acid concentrations and leukocyte count remained increased at 56 μmol/L and 20,700/μL, respectively. Diagnostic imaging to further investigate a portosystemic shunt was declined by the owner. Because of the foal's lack of response to treatment and persistently increased blood ammonia and bile acid concentrations, euthanasia was elected.

Postmortem examination disclosed a smaller than normal liver with an approximately 8-cm partially organized thrombus that completely occluding the portal vein (Fig 1). The thrombus was adhered to underlying eroded endothelium (Fig 2). Histologically, the thrombus was formed by laminated fibrin and red blood cells (lines of Zahn) with entrapped white blood cells, primarily degenerate neutrophils. The remaining endothelial cells were reactive and there was mild fibroplasia at the base of the thrombus. There was no evidence of features that would indicate a lesion of >10–14 days duration: hemosiderin-laden macrophages within the thrombus, endothelial covering of the surface of the thrombus, recanalization, or budding of the endothelium from the tunica intima.[1] Within the liver parenchyma, hepatocytes were moderately attenuated with condensation of the hepatic architecture, making the portal tracts appear closer together, a finding suggestive of decreased hepatic blood flow. No macroscopic shunt vessels were identified despite thorough dissection. Findings of mild nonsuppurative portal hepatitis and portal tract atrophy were similar to those noted on antemortem liver biopsy. Severe, diffuse, pyogranulomatous lymphadenitis was noted in the mesenteric lymph nodes. Affected lymph nodes were enlarged and contained thick, purulent material, from which Rhodococcus equi was cultured. No R. equi pulmonary lesions were identified. Histologic examination of the brain, heart, kidneys, spleen, and intestines was unremarkable, and bacterial culture of tissues from the liver, lung, and intestines yielded no clinically relevant pathogens. The putative genesis of the portal vein thrombus was hematogenous translocation of bacteria and inflammatory mediators from the mesenteric lymph nodes inducing prothrombotic, antifibrinolytic shifts in hemostasis within the portal vasculature, ultimately resulting in thrombus formation.

image

Figure 1. Necropsy photograph showing an approximately 8-cm thrombus within the portal vein (forceps), extending into the right lobe of the liver.

Download figure to PowerPoint

image

Figure 2. Necropsy photograph showing roughened portal vein endothelium. The thrombus has been removed.

Download figure to PowerPoint

Portal thrombosis and subsequent hyperammonemic encephalopathy have not been reported previously in a foal. The portal vein is a primary component of the splanchnic circulatory system and carries blood from the gastrointestinal tract, spleen, and pancreas to the liver for detoxification and processing by the reticuloendothelial system.[2] Portal vein thrombosis has been reported in both humans and animals as a sequela of sepsis, hypercoagulability, neoplasia, and inflammation,[3-7] including a case report describing portal vein thrombosis in association with septic mesenteric lymphadenitis.[8] Common underlying conditions in adults are hepatic cirrhosis, neoplasia, and myeloproliferative disorders,[3, 6] whereas in children, infectious etiologies such as sepsis or omphalitis are observed more frequently.[4] Similar septic and inflammatory etiologies are observed in dogs, and portal vein thrombosis has been reported as a sequela of pancreatitis, peritonitis, amyloidosis, ehrlichiosis, and abdominal neoplasia.[7]

Despite being responsible for two thirds of total hepatic blood flow, complete thrombosis of the portal vein rarely is symptomatic.[3, 4, 6, 7] The body's ability to compensate for impaired portal circulation likely is caused by 2 compensatory mechanisms that act to restore hepatic blood flow in response to portal obstruction. The 1st mechanism is the arterial “buffer” response, which consists of immediate vasodilatation of the hepatic arterial bed.[6] The 2nd mechanism is the rapid development of portoportal and portosystemic collateral veins to provide an alternate route for portal circulation.[3, 4, 6, 7] Although collateral neovascularization is essential for restoring circulation and preventing portal hypertension, if the collateral vessels are portocaval in nature (bypassing hepatic circulation), the blood will not undergo normal hepatic detoxification before return to systemic circulation, and hyperammonia will ensue. Hyperammonemic encephalopathy has only been reported rarely as a complication of portal vein thrombosis in any species, and is associated with complete obstruction of portal blood flow and development of portocaval shunts.[5, 9-11]

Portal vein occlusion has been reported in 2 horses. In a yearling Thoroughbred gelding with recurrent signs of encephalopathy and persistently increased blood ammonia concentration, an arteriovenous anomaly was identified on necropsy that was hypothesized to have altered the portal vascular blood flow and contributed to development of a portal vein thrombus.[9] In a geriatric Quarter Horse mare displaying lethargy, mania, and blindness, postmortem examination identified a gastric adenocarcinoma with hepatic metastases occluding the portal vein, causing obstruction of blood flow and subsequent hyperammonemic encephalopathy.[5]

Inflammation and sepsis are known initiators of systemic coagulation pathways by activation of the intrinsic coagulation cascade by circulating proinflammatory mediators such as endotoxin, tumor necrosis factor-α (TNF-α), lipoproteins, and growth factors. Activation of endothelial cells and circulating monocytes stimulates expression of tissue factor, an important initiator of thrombin formation in both health and disease. In the septic patient, systemic hypercoagulability is potentiated by an overall reduction in endogenous anticoagulant factors including tissue factor pathway inhibitor, antithrombin III (ATIII), and activated protein C (aPC). In addition, normal fibrinolytic pathways are impaired by increased concentrations of circulating plasminogen activator inhibitor 1 (PAI-1) and uninhibited activity of thrombin activatable fibrinolysis inhibitor.[12, 13] Experimental bacteremia and endotoxemia induce intravascular fibrin deposition in kidneys, lungs, liver, and brain, manifesting clinically as disseminated intravascular coagulation (DIC), a syndrome frequently observed in septicemic and endotoxemic patients.[13] Consumptive coagulopathies have been observed in septicemic foals,[14-17] and in 1 study, evidence of DIC and microvascular thrombosis were identified in the tissues of 28/32 septic nonsurviving foals.[15] When compared with healthy foals, septic foals have lower aPC and ATIII activities and higher PAI-1, TNF-α, and interleukin-6 (IL-6) activities, suggesting that sepsis induces prothrombotic, antifibrinolytic shifts in hemostasis that may contribute to systemic hypercoagulation and DIC.[15]

Rhodococcus equi is a well-recognized pathogen of foals aged 3 weeks to 6 months.[18, 19] In addition to the classic presentation of pyogranulomatous pneumonia with multifocal pulmonary abscesses, there is a high prevalence of extrapulmonary manifestations associated with R. equi infection, identified in 74% of 150 foals with R. equi infections in 1 report.[20] In that same report, abdominal lymphadenitis was frequently observed and identified in 17% of foals with R. equi infection.[20] Extrapulmonary R. equi disorders may occur without concurrent pneumonia,[18-20] as was observed in the case reported here. Persistent or intermittent bacteremia with R. equi likely plays a role in the pathogenesis of metastatic infection and systemic inflammation,[18-20] and may have contributed to hypercoagulability and subsequent portal vein thrombosis in this foal.

Ammonia is produced primarily in the gastrointestinal tract by the deamination of amino acids by urease-producing enteric bacteria. Approximately 80% of enteric ammonia is absorbed from the gastrointestinal tract into the portal circulation, where it is then detoxified in the liver by conversion into urea. Hyperammonemia in horses develops secondary to decreased hepatic clearance, increased intestinal production and absorption, or decreased renal excretion of ammonia.[5, 9, 21-23] The hyperammonemic encephalopathy observed in the foal reported here was likely a sequela to development of portocaval collateral circulation in response to portal obstruction. Although cerebrospinal fluid ammonia concentration was not measured, the foal's clinical signs were consistent with those reported in other cases of hyperammonemic encephalopathy, which include obtundation, head pressing, wandering, propulsive walking, yawning, cortical blindness, and maniacal behavior.[5, 9, 21-23] The exact pathophysiologic mechanism of hyperammonemic encephalopathy is poorly understood, but it is likely a combination of cerebral edema secondary to glutamine accumulation, blood-brain barrier disruption, and abnormalities in both the GABAergic and benzodiazepine pathways.[24] Alzheimer type II astrocytosis, the histologic hallmark of hepatic encephalopathy, was not observed in this foal, but this finding varies considerably with chronicity and clinical severity, and is best observed in chronic rather than acute cases of hyperammonemia.[25]

The E. coli cultured from the liver biopsy is of unknown clinical relevance, but likely resulted from impaired hepatic clearance of enteric pathogens secondary to abnormal portal circulation. Sample contamination is another plausible explanation, and would be supported by the lack of suppurative inflammation noted on histopathologic examination. In either scenario, it is unlikely that a bacterial infection contributed to this foal's encephalopathy, because there was no additional evidence of bacterial hepatitis or hepatocellular dysfunction, and portal vein thrombosis alone has been shown to be sufficient to cause hyperammonemic encephalopathy in human patients without intrinsic hepatic disease.[11]

The cause of this foal's neonatal diarrhea was not determined. Although epidemiological evidence suggests that foals can become infected with R. equi early in life, clinical disease is not apparent until weeks to months later, and neonatal diarrhea is not a recognized sequela to infection.[18-20] Whether or not this foal's neonatal diarrhea contributed to subsequent R. equi infection and development of portal vein thrombosis at 2 months of age is unknown.

Weaknesses of this case report include lack of bacterial culture of the thrombus, which may have provided valuable insight into its underlying pathogenesis and possible association with concurrent R. equi lymphadenitis. Furthermore, although this foal was treated empirically with broad spectrum antimicrobials for hyperammonemia of suspected hepatic origin, in light of the postmortem findings, antimicrobials directed specifically at R. equi would have been the ideal choice, and would have been supported by this foal's age, leukocytosis, and hyperfibrinogenemia.

The findings in this case should prompt clinicians to consider portal vein thrombosis in the differential diagnosis when evaluating foals with hyperammonemic encephalopathy. In addition, recognition of clinical thrombosis or systemic hypercoagulability in any foal warrants thorough investigation for underlying inflammation or sepsis.

Acknowledgment

  1. Top of page
  2. Acknowledgment
  3. References

Conflict of Interest: Authors disclose no conflict of interest.

Footnotes
  1. 1

    Pfizerpen, Pfizer Animal Health, New York, NY

  2. 2

    Amiglyde-V, Fort Dodge Animal Health, Fort Dodge, IA

  3. 3

    Flagyl, Pfizer Animal Health

  4. 4

    Flunixamin, Pfizer Animal Health

  5. 5

    Azium, Schering-Plough Animal Health, Summit, NJ

  6. 6

    Abbott Laboratories, Inc., Abbott Park, IL

  7. 7

    Gentafuse, Butler Schein Animal Health, Dublin, OH

  8. 8

    Elevate W.S., Kentucky Performance Products, Versailles, KY

References

  1. Top of page
  2. Acknowledgment
  3. References